Increased intracellular calcium triggered by immune mechanisms in amyotrophic lateral sclerosis

Stanley H. Appel, R. Glenn Smith, N. Alexianu, Laszlo Siklos, Joseph Engelhard, Luis V. Colom, Enrico Stefan

Research output: Contribution to journalReview articlepeer-review

40 Scopus citations


Although the cause of motor neuron degeneration and death in amyotrophic lateral sclerosis (ALS) is unknown, recent evidence suggests a prominent role for increased intracellular calcium, possibly triggered by autoimmune mechanisms. The presence in ALS patients of paraproteinemias, lymphomas, lymphoid cells in the central nervous system (CNS) and the availability of animal models of immune-mediated motor neuron disease provide circumstantial evidence for autoimmunity. Direct evidence derives from the demonstration that ALS IgGs bind to voltage-gated calcium channels in 75% of sporadic cases, but not in familial ALS cases, and that ALS IgGs increase N-type and P-type calcium currents in neuronal cells and in lipid bilayers. These same ALS IgGs are cytotoxic for a motor neuron cell line (VSC 4.1) in vitro. In addition, following passive transfer to mice in vivo, ALS IgGs produce ultrastructural and calcium changes in synaptic vesicles and mitochondria of motor axon terminals, as well as in rough endoplasmic reticulum and Golgi complex of motor neuron perikarya, but not in sensory neurons or Purkinje cells. The reason for the selective vulnerability of motor neurons is not clearly defined, but a prominent possibility is the physiological absence in motor neurons of the calcium-binding proteins calbindin-D(28k) and parvalbumin. These studies emphasize the central role of increased intracellular calcium in motor neuron cell death in sporadic ALS, and the role of autoimmunity in triggering such increases.

Original languageEnglish (US)
Pages (from-to)368-374
Number of pages7
JournalClinical Neuroscience
Issue number6
StatePublished - 1995
Externally publishedYes


  • ALS
  • autoimmunity
  • calbindin-D(28k)
  • calcium
  • calcium channels
  • parvalbumin

ASJC Scopus subject areas

  • Neuropsychology and Physiological Psychology
  • Neuroscience(all)


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